Valdecoxib

Usage

• Valdecoxib was indicated for the relief of signs and symptoms of osteoarthritis and adult rheumatoid arthritis, and for the treatment of primary dysmenorrhea (painful menstruation). It was also studied for other types of acute pain (e.g., post-surgical).
• Pharmacological classification: Nonsteroidal anti-inflammatory drug (NSAID), specifically a COX-2 inhibitor.
• Mechanism of Action: Valdecoxib works by selectively inhibiting cyclooxygenase-2 (COX-2), an enzyme responsible for producing prostaglandins that mediate inflammation and pain. This targeted action reduces pain and inflammation with theoretically less impact on COX-1, which is involved in gastrointestinal protection. However, COX-2 is also involved in other physiological processes.

Alternate Names

• Bextra (brand name, no longer available)

How It Works

• Pharmacodynamics: Valdecoxib exerts its analgesic and anti-inflammatory effects by specifically targeting COX-2, thereby reducing prostaglandin synthesis. It does not inhibit platelet aggregation, unlike some non-selective NSAIDs.

• Pharmacokinetics:

  • Absorption: Valdecoxib is well absorbed orally, reaching peak plasma concentrations in approximately 3 hours. The absolute bioavailability is around 83%.
  • Metabolism: Extensively metabolized in the liver primarily by CYP3A4 and CYP2C9 enzymes, also via glucuronidation. The major active metabolite is 1-hydroxyvaldecoxib.
  • Elimination: Primarily eliminated through hepatic metabolism with less than 5% excreted unchanged in urine and feces.

• Mode of Action: Binds selectively to the COX-2 enzyme, inhibiting its activity and preventing the conversion of arachidonic acid to prostaglandin H2, the precursor to other prostaglandins that mediate inflammation and pain.

• Elimination Pathways: Predominantly hepatic metabolism, with minor renal excretion.

Dosage

Note: Valdecoxib was withdrawn from the market in 2005 due to safety concerns (increased risk of cardiovascular events and serious skin reactions). The following dosage information reflects the recommendations when the drug was available.

Standard Dosage

Adults:

• Osteoarthritis/Rheumatoid Arthritis: 10 mg once daily. Some patients may benefit from 20 mg once daily (maximum recommended dose).
• Primary Dysmenorrhea: 20 mg twice daily as needed. An additional 20 mg could be taken on the first day if needed (total maximum 40 mg on day one), but thereafter, the maximum dose was 40mg daily.

Children:

• Not evaluated or recommended for use in children under 18 years of age.

Special Cases:

• Elderly Patients: For patients over 65, and especially those weighing less than 50 kg, initiate therapy at the lowest recommended dose (10 mg once daily for osteoarthritis and rheumatoid arthritis).

• Patients with Renal Impairment: No dose adjustment generally necessary for mild to moderate renal impairment, but caution is advised. Use not recommended in advanced renal disease.

• Patients with Hepatic Dysfunction: No dose adjustment for mild hepatic impairment. Initiate treatment with caution at a lower dose in moderate hepatic impairment (maximum 20 mg daily for primary dysmenorrhea or osteoarthritis/rheumatoid arthritis. Contraindicated in severe hepatic impairment.

Clinical Use Cases

• The drug is no longer available, therefore no clinical use cases are relevant.

Dosage Adjustments

• See “Special Cases” above for dose modifications.

Side Effects

Common Side Effects

• Diarrhea, nausea, upset stomach, headache, indigestion, stomach cramps, upper respiratory tract infection, back pain, dizziness, gas, muscle pain, rash, stuffy nose, edema/swelling.

Rare but Serious Side Effects

• Cardiovascular events (e.g., myocardial infarction, stroke), serious skin reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome), gastrointestinal bleeding, ulceration, perforation, anaphylaxis, angioedema, renal failure, hepatitis, pancreatitis.

Long-Term Effects

• Potential for gastrointestinal complications, cardiovascular risks with prolonged use.

Adverse Drug Reactions (ADR)

• Serious skin reactions, severe allergic reactions, cardiovascular events.

Contraindications

• Hypersensitivity to valdecoxib or sulfonamides.
• History of asthma, urticaria, or allergic-type reactions after aspirin or NSAID use.
• Active peptic ulceration or gastrointestinal bleeding.
• Third trimester of pregnancy and breastfeeding.
• Severe hepatic dysfunction.
• Inflammatory bowel disease.
• Severe congestive heart failure (NYHA III-IV)
• Coronary artery bypass graft surgery (perioperative pain)

Drug Interactions

• Aspirin (increased risk of GI bleeding), ACE inhibitors, furosemide, thiazide diuretics, warfarin, lithium, other NSAIDs, some anticonvulsants (phenytoin), ketoconazole, fluconazole, oral contraceptives, diazepam, glyburide, omeprazole.

Pregnancy and Breastfeeding

• Pregnancy: Contraindicated in the third trimester. Not recommended in the first two trimesters unless potential benefit outweighs the risk. Avoid if trying to conceive. May cause premature closure of the ductus arteriosus.
• Breastfeeding: It is not known if valdecoxib is present in human breast milk. Because of potential risk to the infant it is not recommended during breastfeeding.

Drug Profile Summary

Valdecoxib was withdrawn from the market due to safety concerns including cardiovascular and dermatological events, therefore no summary is clinically relevant.

Popular Combinations

• Not applicable as the drug is no longer on the market.

Precautions

• See Contraindications, Drug Interactions, and Pregnancy and Breastfeeding for specific warnings.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Valdecoxib?

A: Valdecoxib is no longer available due to safety concerns. When it was available, the dosage for osteoarthritis/rheumatoid arthritis was 10 mg once daily (up to 20 mg), and for primary dysmenorrhea, 20 mg twice daily as needed (up to 40 mg on the first day).

Q2: Why was Valdecoxib withdrawn from the market?

A: Valdecoxib was withdrawn due to an increased risk of cardiovascular events (heart attack, stroke) and serious, sometimes fatal, skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis).

Q3: What are the main side effects of Valdecoxib?

A: Common side effects included gastrointestinal issues (diarrhea, nausea, abdominal pain), headache, dizziness, and rash. Serious side effects included cardiovascular events and severe skin reactions.

Q4: What are the alternatives to Valdecoxib?

A: Other NSAIDs (including other COX-2 inhibitors like celecoxib) or other pain relievers, depending on the specific condition.

Q5: Can Valdecoxib be used during pregnancy?

A: Valdecoxib was contraindicated in the third trimester and generally not recommended during pregnancy due to potential risks to the fetus.

Q6: How does Valdecoxib differ from traditional NSAIDs?

A: Valdecoxib selectively inhibits COX-2, which theoretically reduces gastrointestinal side effects compared to non-selective NSAIDs that inhibit both COX-1 and COX-2. However, COX-2 inhibition carries a higher risk of cardiovascular events.

Q7: Does Valdecoxib interact with other medications?

A: Yes, Valdecoxib can interact with numerous medications, including aspirin, warfarin, some diuretics, and others.

Q8: Can I take Valdecoxib if I am allergic to sulfa drugs?

A: Valdecoxib was contraindicated in patients with sulfonamide allergy due to its chemical structure.

Q9: How quickly does Valdecoxib work for pain relief?

A: The onset of pain relief varied depending on the condition treated and the individual, but it could provide relatively rapid pain relief in certain cases (e.g., acute pain, dysmenorrhea).